Project Summary/Abstract Therapeutic management of lung disorders hallmarked by the loss-of-function of the Cystic Fibrosis (CF) Transmembrane conductance Regulator (CFTR) leading to CF are challenged by genetic and epigenetic diversity found in the CF population. Given the Precision Medicine Initiative (All of Us for You (https://allofus.nih.gov/) and the large amount of genomic and phenomic diversity found in patients, it is now generally recognized that we must find new approaches to address the complexity in CF presentation in the clinic. This will require an understanding of fundamental principles dictating disease onset at birth, defined by familial genetic variation, and its progression, influenced by epigenetic programs, both unique to the individual. This proposal is about understanding the role of genetic and epigenetic diversity in CF in response to Histone DeACetylase (HDAC) activity. We have shown these relationships to be responsive to the activity of HDACs, proteins that manage the acetylation/deacetylation balance of the genome and the proteome (the epigenome) to integrate the complex functions linking the genome to the proteome and phenome. Based on the premise that the genome and epigenome are sensitive to manipulation(s) that will favor increased functionality of the CFTR variant fold, the objective of this proposal is to mechanistically define the impact of HDAC modulation on CFTR function observed at the bench and the bedside. We hypothesize that CF can be best understood based on the rationale that disease can be defined by the collective of variation found in the CF population that alters CFTR sequence-to-function-to-structure relationships in the individual as now described using Variation Spatial Profiling (VSP) and the new principle of Spatial CoVariance (SCV) (Wang and Balch, 2018, In press). It is the objective of this proposal to apply VSP/SCV to analysis of the role of the epigenome in CF. Key goals to be achieved in this proposal are to 1) define molecular, cellular and physiological states that 2) describe the role of genetic/epigenetic/proteomic diversity in the CF population to 3) provide a sequence-to-function-to-structure characterization of disease in the individual. Aim 1 will explore the impact of HDAC inhibitors (HDACi) to define, from a biochemical/genetic diversity perspective, how variation across the entire CF population will respond to rebalancing of acetylation/deacetylation dynamics. Aim 2 will focus on the role of HDAC7 in the management of CF genetic diversity using molecular, biochemical and cellular approaches. Aim 3 will analyze the role of select HDAC7-sensitive CFTR interactors to address their role in the management of CF variation from an epigenetic perspective. We hypothesize that the completion of these Aims will describe relationships in the population that define the epigenome-linked genome features that impact progression of CF in the individual. Our integrated genome/epigenome/proteome platform will advance our understanding of the contribution of genetic diversity in the progression and management of CF as a complex disease.